rectal adenocarcinoma rectal cancer
Conditions
Interventions
Subjects can be randomized in one of the following three arms:
- Arm A: Subjects will receive neoadjuvant chemoradiotherapy and concomitant
L-BLP25 vaccinations preceded by a single dose of CPA.
- A
Sponsors
Merck
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Male and female subjects with histologically documented resectable rectal adenocarcinoma in stages II-IV. 2. Availability of 3 formalin-fixed paraffin-embedded (FFPE) tumor specimens (snips biopsies obtained by forceps or similar procedure resulting in a representative biopsy tissue of sufficient size) for central analysis (baseline tumor sample). 3. Indication to receive neoadjuvant concomitant chemoradiotherapy consisting of a radiation dose of 45-52 Gy and capecitabine 825 mg/m² orally twice daily for the duration of radiotherapy. Slight modifications of the dosing regimen are acceptable based on the local standard of care. The use of an equivalent schedule based on 5-fluorouracil (5-FU) is acceptable based on the local standard of care. Indication for resection/surgery. 4. MRI small pelvis / CT thorax/abdomen (or X-ray thorax) to document absence of metastatic disease. If imaging is older than 6 weeks prior to randomization a waiver must be obtained from the Sponsor. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Written informed consent. 7. * 18 years of age.
Exclusion criteria
Exclusion criteria: 1. Previous chemotherapy and/or previous radiotherapy of the pelvic region. 2. Relapsing disease. 3. Previous vaccination with any MUC1 vaccine and other therapeutic cancer vaccines. 4. Previous organ transplantation (bone marrow or solid organs). 5. Subjects with metastatic disease (except for solitary, resectable liver or lung metastases). When appropriate, resection of the solitary liver or lung metastases cannot be performed during trial treatment but should be performed either before or after trial treatment. 6. Inadequate hematological function (i.e. platelet count 2.5 times upper limit of normal [ULN], or aspartate aminotransferase [AST] > 2.5 x ULN, or bilirubin * 1.5 x ULN). 8. Inadequate renal function (i.e. serum creatinine * 1.5 x ULN). 9. Autoimmune diseases. 10. A recognized immunodeficiency disease including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects who have hereditary or congenital immunodeficiencies. 11. Clinically significant cardiac disease, e.g. New York Heart Association classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, myocardial infarction in the previous 6 months as confirmed by medical history and an electrocardiogram (ECG).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| There are three primary endpoints: one intratumoral immune parameter and two peripheral antigen-specific immune parameters (response to MUC1 and CEA). The intratumoral immune response will be evaluated by immunohistochemical analysis of tumor-infiltrating lymphocytes (TILs) in tumor specimens. Effector T cells, especially CD8+ and CD4+ cells, will be analyzed inside the tumor by immunohistochemistry (IHC). The peripheral antigen-specific response will be tested by ELISpot, evaluating the Interferon (IFN)-gamma secretion of mononuclear cells in response to MUC1 and CEA. The maximal value of each of the measurements at Week 5, Week 11-13 (pre-surgery), and Week 16-18 (Followup / End-of-Trial visit) will be evaluated. | — |
Secondary
| Measure | Time frame |
|---|---|
| Assessments in tumor specimens: - Peritumoral Immune Response (peritumoral IR): immunohistochemical analysis of TILs in the lymphoid infiltrate at the margin of the tumor (peritumoral infiltrate). - IHC expression of regulatory T cells (CD127-FOXP3+) and myeloid-derived suppressor cells (CD33+CD14-). - IHC expression of other immune cells such as NK cells (CD3-CD56+), B cells (CD19+), plasmacytoid dendritic cells (pDC) (CD123+), and myeloid dendritic cells (mDC) (CD11c+). - IHC expression of chemokines CXCR3, CCR5. Assessments in the blood: - Fluorescence analysis cell sorter (FACS) phenotypic characterization of T cells (CD3+CD4+ and CD3+CD8+) and of markers of activation and proliferation (ICOS, CD27, Ki67, BTLA, PD-1). - FACS phenotypic characterization of regulatory cells such as CD3+CD4+ (or CD8+) CD45RA+CD25+FoxP3+CD127 T cells and myeloid-derived suppressor cells (CD11b+CD33+CD66b+ HLA-DR*). - FACS phenotypic characterization of cytotoxic cells such as cytotoxic T lymphocyte (CTL; CD3+CD8+) and NK cells (CD3-CD56+) and their killing activity (Granzyme B, Perforin, CD107a). - FACS phenotypic characterization of B cells (CD19+), pDC (CD123+), and mDC (CD11c+). - Chemokine profile including CCL22, CXCL9 in blood and CXCR3, CCR7, CCR5 in CD4 and CD8 cells. - MHC class-I tetramer analysis to detect MUC1- and CEA-specific T cells (according to feasible HLA). - Intracellular staining for IFN-gamma and tumor necrosis factor (TNF)-alpha in CD4 cells and CD8 T cells. - Cytokine profile (e.g., interleukin [IL]1RA, IL-6, IL- 8, IL-10, IL-12p70, IFN-gamma, TNF-alpha, IL-17) by Luminex and/or immunoassay. - Pre-operative circulating serum CEA levels (at baseline and during treatment). - Assessment of DTH response of L-BLP25 prior to surgery. | — |
Countries
Netherlands
Outcome results
None listed